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Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD)
FASEB J. 2018 May;32(5) :2735-2746
PMID: 29401581    PMCID: PMC5901382    URL: https://www.ncbi.nlm.nih.gov/pubmed/29401581
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Abstract
Autosomal-dominant polycystic kidney disease (ADPKD) is associated with progressive formation of renal cysts, kidney enlargement, hypertension, and typically end-stage renal disease. In ADPKD, inherited mutations disrupt function of the polycystins (encoded by PKD1 and PKD2), thus causing loss of a cyst-repressive signal emanating from the renal cilium. Genetic studies have suggested ciliary maintenance is essential for ADPKD pathogenesis. Heat shock protein 90 (HSP90) clients include multiple proteins linked to ciliary maintenance. We determined that ganetespib, a clinical HSP90 inhibitor, inhibited proteasomal repression of NEK8 and the Aurora-A activator trichoplein, rapidly activating Aurora-A kinase and causing ciliary loss in vitro. Using conditional mouse models for ADPKD, we performed long-term (10 or 50 wk) dosing experiments that demonstrated HSP90 inhibition caused durable in vivo loss of cilia, controlled cystic growth, and ameliorated symptoms induced by loss of Pkd1 or Pkd2. Ganetespib efficacy was not increased by combination with 2-deoxy-d-glucose, a glycolysis inhibitor showing some promise for ADPKD. These studies identify a new biologic activity for HSP90 and support a cilia-based mechanism for cyst repression.-Nikonova, A. S., Deneka, A. Y., Kiseleva, A. A., Korobeynikov, V., Gaponova, A., Serebriiskii, I. G., Kopp, M. C., Hensley, H. H., Seeger-Nukpezah, T. N., Somlo, S., Proia, D. A., Golemis, E. A. Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD).
Notes
1530-6860 Nikonova, Anna S Deneka, Alexander Y Kiseleva, Anna A Korobeynikov, Vladislav Gaponova, Anna Serebriiskii, Ilya G Kopp, Meghan C Hensley, Harvey H Seeger-Nukpezah, Tamina N Somlo, Stefan Proia, David A Golemis, Erica A P30 DK079310/DK/NIDDK NIH HHS/United States Journal Article United States FASEB J. 2018 Jan 10:fj201700909R. doi: 10.1096/fj.201700909R.